Pain
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Approximately 10% to 20% of individuals with previous SARS-CoV-2 infection may develop long-COVID syndrome, characterized by various physical and mental health issues, including pain. Previous studies suggested an association between small fibre neuropathy and pain in long-COVID cases. In this case-control study, our aim was to identify small fibre neuropathy in patients experiencing painful long-COVID syndrome. ⋯ This case-control study showed that approximately 50% of patients experiencing painful long-COVID syndrome had small fibre neuropathy. However, in our patient cohort, this specific post-COVID-19 complication was unrelated to demographic and COVID-19 clinical variables. Approximately half of our sample of patients with painful long-COVID symptoms met diagnostic criteria for small fibre neuropathy.
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In humans and animals, high-frequency electrocutaneous stimulation (HFS) induces an "early long-term potentiation-like" sensitisation, where synaptic plasticity is underpinned by an ill-defined interaction between peripheral input and central modulatory processes. The relative contributions of these processes to the initial pain or nociceptive response likely differ from those that underpin development of the heightened response. ⋯ Application of a distant noxious conditioning stimulus during HFS did not alter perceived primary or secondary hyperalgesia in humans or the development of primary or secondary neuronal hyperexcitability in rats compared with HFS alone, suggesting that, upon HFS-response initiation in a healthy nervous system, excitatory signalling escapes inhibitory control. Therefore, in this model, dampening facilitatory mechanisms rather than augmenting top-down inhibitions could prevent pain development.
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Tendon injury produces intractable pain and disability in movement, but the medications for analgesia and restoring functional integrity of tendon are still limited. In this study, we report that proteinase-activated receptor 2 (PAR2) activation in dorsal root ganglion (DRG) neurons contributes to chronic pain and tendon histopathological changes produced by Achilles tendon partial transection injury (TTI). Tendon partial transection injury increases the expression of PAR2 protein in both somata of DRG neurons and their peripheral terminals within the injured Achilles tendon. ⋯ Vitamin B complex (VBC), containing thiamine (B1), pyridoxine (B6), and cyanocobalamin (B12), is effective to ameliorate TTI-induced pain, inhibit ectopic nerve sprouting, and accelerate tendon repair, through suppressing PAR2 activation. These findings reveal a critical role of PAR2 signaling in the development of chronic pain and histopathological alterations of injured tendon following Achilles tendon injury. This study suggests that the pharmaceuticals targeting PAR2, such as VBC, may be an effective approach for the treatment of tendon injury-induced pain and promoting tendon repair.
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Randomized Controlled Trial
Characterizing the opioidergic mechanisms of repetitive transcranial magnetic stimulation-induced analgesia: a randomized controlled trial.
Repetitive transcranial magnetic stimulation (rTMS) is a promising technology to reduce chronic pain. Investigating the mechanisms of rTMS analgesia holds the potential to improve treatment efficacy. Using a double-blind and placebo-controlled design at both stimulation and pharmacologic ends, this study investigated the opioidergic mechanisms of rTMS analgesia by abolishing and recovering analgesia in 2 separate stages across brain regions and TMS doses. ⋯ In the DLPFC, double but not the first TMS session induced significant pain reduction in the saline condition, resulting in less pain compared with the naloxone condition. In addition, TMS over the M1 or DLPFC selectively increased plasma concentrations of β-endorphin or encephalin, respectively. Overall, we present causal evidence that opioidergic mechanisms are involved in both M1-induced and DLPFC-rTMS-induced analgesia; however, these are shaped by rTMS dosage and the release of different endogenous opioids.
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Developments in human cellular reprogramming now allow for the generation of human neurons for in vitro disease modelling. This technique has since been used for chemotherapy-induced peripheral neuropathy (CIPN) research, resulting in the description of numerous CIPN models constructed from human neurons. This systematic review provides a critical analysis of available models and their methodological considerations (ie, used cell type and source, CIPN induction strategy, and validation method) for prospective researchers aiming to incorporate human in vitro models of CIPN in their research. ⋯ Furthermore, treatment effects were almost exclusively validated by the acute effects of chemotherapeutics on neurite dynamics and cytotoxicity parameters, enabling the extrapolation of the half-maximal inhibitory concentration for the 4 most used chemotherapeutics. Overall, substantial heterogeneity was observed in the way studies applied chemotherapy and reported their findings. We therefore propose 6 suggestions to improve the clinical relevance and appropriateness of human cellular reprogramming-derived CIPN models.